Chapter 27. Amenorrhea: Berek & Novak's Gynecology 14 Edition (P 1035 1068) R3 Jung Mi Byun

Chapter 27.
Amenorrhea
Berek & Novak’s Gynecology

14th edition (p 1035~1068)
R3 Jung Mi Byun
Overview
 Primary amenorrhea
: absence of menses
– at age 13years when there is no visible secondary sexual

characteristic development
– at age 15years in the presence of normal secondary sexual

characteristics
 Secondary amenorrhea
– A woman who has previously menstruated
– absence of menstruation for three normal menstrual cycles
or 6 months
Overview
 Premature gonadal failure occurs in conjunction with primary
amenorrhea
– associated with genetic abnormalities (30%)
 Diagnosis
– History
– Physical examination
• 2nd sexual characteristics
• anatomic abnormalities (relatively few)
– Lab
• hCG
• FSH (differentiate between hypergonadotropic and
hypogonatropic forms of hypogonadism)
Overview
 Treatment
<Goal >
– correcting the primary cause of amenorrhea
– to initiate and maintain secondary sexual characteristics
– maintenance of bone mass
– Ovulation induction for patients desiring pregnancy
 Mehthod
– medical or surgical therapy
– hormone replacement
Overview
Anterior suprachiasmatic nucleus
Posterior arcuate nucleus
Normal menstrual cycle

Overview
 Amenorrhea Mechanism
– any of the components : nonfunctional
hypothalamus, pituitary, ovary, outflow tract, feedback mechanism
→ bleeding cannot occur. (Amenorrhea)
 Amenorrhea : 3~4% of reproductive age women, not pregnant.

Decision tree for evaluation of amenorrhea.
Secondary sexual
characteristics
Absent Present
Physical exam HCG - HCG +
Normal Absent uterus Pregnancy

Primary
•5α-reductase
) deficiency No Yes
FSH level
•17-20 desmolase
deficiency
•17α-hydroxylase
deficiency (all with
XY karyotype)
High Normal
Karyotype Karllman’s syndrome

Physiology delay
Disorders of low
XX estrogen status
Y line before puberty
Turner’s (XO)
Primary
No Yes
Secondary if risk of Physical exam

endometial scarring
advise HSG &
culrutres to exclude
Normal Abnormal
Asherman’s, cervical
stenosis and infection
TSH, PRL, FSH, Mullerian anomaly

Clinical evaluation Androgen insensitivity
of estrogen status True hermaphroite
Normal TSH Abnormal TSH
High PRL Hyperthyroidism

Hypothyroidism
Normal PRL Hyperprolactinemia

Normal PRL
Normal FSH High FSH
Normal estrogen Low estrogen Ovarian failure-

chromosomal
radiaton
chemotherapy
Chronic anovulatory Ovarian neoplasm  Feedback disorders Neurological exam infection
 Obesity CT/MRI, EEG autoimmune
Polycystic ovarian Grandulosa cell  Cushing’ syndrome Galactosemia
syndrome androgen-  Androgen-secreting Savage syndrome
secreting adrenal tumors Idiopathic
Idiopathic  Congenital adrenal
hyperplasia
Normal Abnormal
Chronic disease Hypothalamic Pituitary-hypothalamic

pulmonary dysfunction lesions
renal Anorexia tumors
liver Exercise-induced infection
diabetes Stress infarction
Addison’s disease Pseudocyesis pituitary failure
Malnutrition Sheehan’s
Diabetic vasculitis
Toxic-lead
 Amenorrhea
without Secondary Sexual Characteristics
 Amenorrhea
with Secondary Sexual Characteristics
and Anatomic Abnormalities
Amenorrhea
 Absence of secondary sexual characteristics

(breast development : 1st sign of estrogen exposure in puberty)
→ woman has never been exposed to estrogen stimulation
 Absence of a uterus suggests certain enzyme deficiencies and i

ndicate the presence of antimullerian hormone (AMH) in an XY in
dividual .
Cause of Primary Amenorrhea
 Hypergonadotropic Hypogonadism
– Genetic Disorders
– Enzyme Deficiencies
– Gonadotropin Receptor Mutation
 Other causes of Primary Ovarian Failure
 Hypogonadotropic Hypogonadism
 Genetic Disorders
 Other Hypothalamic / Pituitary Dysfunctions

Table 27.1 Amenorrhea Associated with a Lack of Secondary Sexual Charateristics
Abnormal physical examination

5α-reductase deficiency in XY individual
17, 20-desmolase deficiency in XY individual
17α-hydroxylase deficiency in XY individual
Hypergonadotropic hypogonadism
Gonadal dysgenesis
Pure gonadal dysgenesis
Partial deletion of X chromosome
Sex chromosome mosaicism
Environmental and therapeutic ovarian toxins
17α-hydroxylase deficiency in XX individual
Galactosemia
Other
Hypogonadotropic hypogonadism
Physiologic delay
Kallmann’s syndrome
Central nervous system tumors
Hypothalamic/pituitary dysfunction
Hypergonadotropic Hypogonadism
 LH, FSH ↑ : d/t decreased negative estrogen feedback.
 Associated with genetic abnormalities

(Approximately 30% of patients with primary amenorrhea)
 Syndrome of gonadal dysgenesis or Turner syndrome
 Other disorder :
– structurally abnormal X chromosomes,
– mosaicism,
– pure gonadal dysgenesis (46,XX and 46,XY with gonadal streaks)
,
– enzyme deficiencies that prevent normal estrogen production,
– Gonadotropin-receptor inactivating mutations
Genetic Disorder
Gonadal Dysgenesis
 Turner syndrome(45,X)
:m/c chromosomal abnormality causing
gonadal failure and primary amenorrhea
P.Ex
– short stature, webbed neck
– shield chest,
– cubitus valgus
– short metacarpals,
– low hair line,
– high arched palate,
– multiple pigmented nevi,
– short fourth metacarpals
Study
– cardiac (30%: coarctaion of the aorta)
– renal (horseshoe kidney),
– autoimmune(thyroiditis)
Genetic Disorder
 Abnormal X Chromosome
– 46, XX individuals with partial deletions of the X chromosome
: variable phenotypes depending on the amount and location of
the missing genetic material
– Deletion of the long arm of the X chromosome(Xq-) Xq13~Xq26

- sexual infantilism
- normal stature
- no somatic abnormalities, no streak gonads
- eunuchoid in appearance, delayed epiphyseal closure (some)
– Deletion of the short arm of the X chromosome (Xp)

: phenotypically similar to individual with Turner syndrome
Genetic Disorder
 Mosaicism
– 45,X/46XX (m/c)
– Clinical finding :taller and fewer abnormalities than pure 45,X
– 20% : spontaneous menstruation (+)
Genetic Disorder
 Pure Gonadal Dysgenesis
– Phenotypically female with sexual infantilism,
– primary amenorrhea,
– normal stature,
– no chromosomal abnormalities (46, XX or 46, XY)
– Gonads
: usually streaks, some development of 2nd sexual characteristics
< Swyer syndrome >

– mutations in the SRY (sex-determining region gene on the Y
chromosome) located at Yp11 result in XY females with
gonadal dysgenesis
– 15~20% of women (46,XY)
Genetic Disorder
 Mixed gonadal dysgenesis

– XY
– Ambiguous genitalia with a streak gonad on one side and a

malformed testis on the opposite
– SRY gene mutation (small proportion )

Enzyme deficiencies
 Congenital Lipoid Adrenal Hyperplasia
– Autosomal recessive disorder
– Cholesterol → Pregnenolone
– Not defect of the P450scc gene
– 15 different mutations in the steroid
ogenic acute regulatory protein(StA
R) : facilitates the transport of chole
sterol from the outer to the inner mit
ochondrial membrane.
– hypoNa, HyperK, acidosis in infancy
– XX, XY(m/c) – no uterus
– phenotype : female
– Genetic cluster : Japanes/Korean an
d Palestinian Arab population
– Tx :mineralocorticoid and glucocort
icoid replacement
Enzyme deficiencies
 17α-Hydroxylase & 17, 20-Desmolase
Deficiency
– mutation in the CYP 17 gene
→ abnormalities in both the 17 α-hy
droxylase and 17, 20-desmolase f
unctions of the protein
– Karyotype : 46, XX 46,XY
(no uterus)
– primary amenorrhea, no 2nd sexua
l characteristic, female phenotyp
e, HTN, hypoK,
– ACTH ↑
– Meneralocorticoid production ↑
→ Na retension, K loss, HTN
– Primordial follicle
– Gonadotropin ↑
Enzyme deficiencies
 Aromatase Deficiency
– Autosomal recessive abnormality
Aromatizing
– Androgen estrogen
– Most mother of affected children
: become virilized during pregnanc
y. → suspected before birth.
– At birth
: female child-clitoromegaly and pos
terior labioscrotal fusion
– At puberty
: no breast development,
primary amenorrhea,
worsening virilization .
absent growth spurt,
delayed bone age,
multicystic ovaries
 Tx : estrogen supply
Gonadotropin receptor Mutations
 Luteinizing Hormone Receptor Mutation
– Inactivation of LH receptors has been identified in XY pseud
ohermaphrodites with primary amenorrhea in the absence o
f secondary sexual characteristics
– caused by homozygous premature stop codon, deletions, a
nd missense mutations in the LHR gene located on chromo
some 2.
 Follicle-stimulating Hormone receptor Mutation

– Autosomal recessive
– single amino acid substitution in the extracellular domain of
the FSH receptor
– Primary or early secondary amenorrhea,
– variable development of secondary sexual characteristics
– high levels of FSH and LH
Other Causes of Primary Ovarian Failure
 Irradiation
 Chemotherapy
with alkylating agents (e.g. cyclophosphamide)
 Combination of radiation and other chemothrapeutic agents
 Galactosemia
Hypogonadotropic Hypogonadism
 Hypothlamus fails to secrete adequate amounts of GnRH
 Pituitary disorder associated with inadequate production or rel

ease of pituitary gonadotropins is present.
 Physical Delay
 Kallmann Syndrome
 Central Nervous System Tumors

Physiologic Delay
 most common manifestation of hypogonadotropic hypogonadis

m
 Amenorrhea
: result from the lack of physical development caused by delayed
reactivation of the GnRH pulse generator
 physiologic delay of puberty are usually short for their chronolo

gic age
 normal for their bone age

Kallmann Syndrome
 2nd most common hypogonadotropic hypogonadism
 insufficient pulsatile secretion of GnRH (Kallmann syndrome), whi

ch has varied modes of genetic transmission
→ leads to deficiencies in FSH and LH
 caused by developmental or genetic defects, inflammatory proces

ses, tumors, vascular lesions, or trauma
 normal height for their age,

Genetic Disorders
 5α-Reductase Deficiency
 Gnoadotropin-releasing Hormone Receptor Mutations
 Follicle-stimulating Hormone Deficiency

Genetic Disorders
5 α-Reductase Deficiency
 XY , virilization at puberty,
 Testes(+) : functioning Y chromosomes
 No mullerian structure, d/t functioning AMH
 Low gnoadotropin level
 D/Dx> androgen insensitivity
: not develop breasts at puberty
5 α-Reductase D  gonadotropin level: low
eficiency
 male differentiation of the urogenital sinus a

nd external genitalia : not
 Normal internal male genitalia
(derived from the wolffian ducts using
testosterone)
 Male pattern hair growth, muscle mass, voic
e deepening
Genetic Disorders
Gonadotropin-releasing Hormone Receptor Mutations
 GnRH receptor : G-protein-coupled receptor
 Abnormal GnRH function
 17% of sporadic cases of idiopathic hypogonadotropic

hypogonadism with normal olfaction
Genetic Disorders
Follicle-stimulating Hormone Deficiency
 FSH deficiency
: treatment for delayed puberty and primary amenorrhea caused
hypoestrogenism.
 FSH↓ LH ↑ : distinguished from other hypoestrogenism
 Low serum androgen levels

: FSH-stimulated follicular development is prerequisite for thecal
cell androgen production
Other Hypothalamic / Pituitary Dysfunctions
 Malnutrition  Marijana
 Malabsorption  Hypothyroidism
 Weight loss  Polycystic ovarian syndrome (PCOS)
 Anorexia nervosa  Cushing syndrome
 Excess ecercise  Hyperprolactinemia
 Chronic disease  infiltrative disorders of the central ner

vous system
 Neoplasia
Amenorrhea
Diagnosis
Treatment
Amenorrhea without Secondary Sexual Characteristics
Diagnosis
 History
– short stature but consistent growth rate,
– a family history of delayed puberty,
– normal physical findings
(including assessment of smell, optic disks, and visual fields)
Physical delay
– Headache,
– visual disturbance,
– short stature, symptoms of diabetes insipidus,
– weakness of limbs
– CNS lesion
Galactorrhea
 Physical Examination
Diagnostic workup
History& P.Ex (-)
Coarctation of the aorta (30%)

FSH
Thyroid dysfunction
→
↑ Echocardiography ↓
: every
(Hypergonadotropic 3~5yrs
hyporog (hypogonadotropic hypogo
→ TFT : yearly
onadism) nadism)
Evaluation for
hearing loss and hypertension
Karyotype
•Serum Progesterone↑(>3.0)
Abnormal Normal •17α-hydroxyprogesterone↓ (0.2ng/mL)
 Turner syndrome 17-α hydroxylase
deficiency •Deoxycorticosterone (DOS)↑
 Partial deletion of the X
chromosome, → ACTH stimulation test
 mosaicision,
: ACTH bolus administration
 Pure gonadal dysgenesis,
 Mixed gonadal dysgenesis →S-progesterone↑
→17α-hydroxyprogesterone ( - )
Diagnostic workup
 if galactorrhea, headaches, visual field defect (+)
→ CT, MRI
 Physiologic delay
– distinguish from insufficient GnRH secretion
– history
– absence of a CNS lesion on CT or MRI
– X-ray : delayed bone age
 Gonadotropin-deficiency
– distinguished from physiologic delay
: response to GnRH stimulation
Physiologic delay Gonadotropin-deficiency
LH : normal LH and FSH ↓
Treatment of Amenorrhea
All forms of gonadal failure

Hypergonadotropic hypogonadism
→ cyclic estrogen and progestin therapy
: to initiate, mature, and maintain 2nd sexual characteristics

prevention of osteoporosis (additional benefit of estrogen)
Initiation  conjugated estrogen 0.625mg/day  short stature : higher estrogen doses (x)
 normal stature : higher estrogen,
(Premarin R ) or after then reduced to the
R
 estradiol 1mg/day (Progynova ) maintenance doses after
several months
 estrogen +progestin (medroxyprogeste Medrosyprogesterone acetate

rone acetate) (Provera ) daily or  2.5mg daily or
R
 5~10mg for 12~14days every
 progesterone 1~2months
Oral micronized progesterone
to prevent unopposed estrogen stimulation R
(utrogestan )
of the endometrium in patients with uterus
 100mg daily or
 200mg for 12~14days every
1~2months
Progesterone suppositories
(progest R )
 50mg daily or
 100mg 12~14days every
1~2 months
 Mosaicism and gonadal streak

: ovulation (+), able to conceive either spontaneously or after
the institution of estrogen replacement therapy
 17α –hydroxylase deficiency

– corticosteroid and estrogen replacement
– If uterus(+) : progestin supply
 Aim of therapeutic measures
: correcting the primary cause of amenorrhea
– Craniopharyngiomas
: resected with a transphenoidal approach or during craniotomy depending on
the size of the tumor
– Germinomas
: radiosensitive ( surgery : rare indication )
– Prolactinomas and hyperprolactinemia

: dopamine agonists (bromocriptine or cabergoline)
– malnutrition, malabsorption, weight loss, anorexia nervosa,

exercise amenorrhea, neoplasia, and chronic disease
: specific therapies
 Aim of therapeutic measures
: correcting the primary cause of amenorrhea
– Hypogonadotropic hypogonadism of hypothalamic origin
- treated with long-term administration of pulsaile GnRH indwelling catheter
and a portable pump
- cyclic estrogen and progestin therapy at least until sexual maturity is
achieved
- hormone replacement to treat hypoestrogenic symptom
- nonestrogenic regimens
eg. Bisphosphomates
(for maintenance of bone mass and prevention of osteoporosis)
– Kallmann syndrome
: hormone replacement
– Physiologic delay
: reassurance that the anticipated development will occur eventually
 Karyotypes contain a Y cell line

(45,X/46, XY mosaicism, or pure gonadal dysgenesis 46, XY)
– Predisposed to gonadal ridge tumor,

such as gonadoblastomas, dysgerminomas, yolk sac tumors
→ remove gonads to prevent malignant transformation

Amenorrhea
with Secondary Sexual Characteristics and
Anatomic Abnormalities
 Causes
– Anatomic Abnormalities
– Androgen insensitivity
– True Hermaphroditismm
Cause of Amenorrhea with 2 nd sexual characteristics and Anatomic Abnormalities
Anatomic causes of Amenorrhea
Secondary sexual characteristics present
Mullerian anomalies
Imperforate hymen
Transverse vaginal septum
Mayer-Rokitansky-Kuster-Hauser syndrome (MRK syndrome)
Androgen insensitivity
True hermaphrodites
Absent endometrium
Asherman’s syndrome
Secondary to prior uterine or cervical surgery
Curettage, especially postpartum
Cone biopsy
Loop electroexcision procedure
Secondary to infections
Pelvic inflammatory disease
IUD-related
Tuberculosis
Schistosomiasis
Mayer-Rokistanky-Kuster-Hauser(M.R.K.H.) syndrome
 XX, female
 result of the mullerian ducts failing to form properly early in embryonic de
velopment, its underlying cause is unknown.
 associated with galactose metabolism
 characterized by congenital absence of the uterus and vagina
 associated with
– anomalies of the kidneys ranging from ectopic to congenital absence,
– skeletal abnormalities
Androgen Insensitivity
 Gynotype : XY
 Phenotype : female
 Male pseudohermaphrodites
(Previously called testicular feminization )
 Defects in the androgen receptor

: gene located on the X chromosome
- absence of the gene that encodes for the androgen receptor
- abnormalities in the binding domains of the receptor
 Develop secondary sexual characteristics but not menses
 Testosterone : range of normal males

☜ antimullerian hormone: present and function (+)
 Internal female (mullerian) structure

(uterus, vagina, fallopian tube) : (-)
 Testes (+) in the abdomen or in inguinal hernias

: normally functioning genes on the Y chromosome
 Blind vaginal pouch and scant or

absent axillary and pubic hair
 Abundant breast development at

puberty
 nipples : immature
 areolae : pale
 Eunuchoidal tendency
(long arms with big hands and feet)
Figure 27. 2
A : A well-developed patient with complete androgen insensitivity
Note the characteristic paucity of pubic hair and well-developed breast
B : Another patient with andtrogen insensitivity syndrome with a contrasting thin
body hiatus. This is a 17-uear-old twin 46,XY.
True Hermaphroditism
 XX, XY and mosaic genotypes
 Both male and female gonadal tissue ( +)
 External genitalia : ambiguous
 Breast development (+)
 15% of XX true hermaphrodites : have SRY translocation

10% of XX true hermaphrodites : have Y chromosomal
mosaicisism within the gonad
Amenorrhea
with Secondary Sexual Characteristics and
Diagnosis
Treatment
Amenorrhea with 2nd sexual characteristics and Anatomic Abnormalities
Diagnosis
Physical Examination Others
Imperforate hymen presence of a bulging membrane USG or MRI : useful
that distend during Valsalva man skeletal malformation exam
euver
IVP for renal abnormalities
Transverse septum blind vaginal pouch in a male pse karyotype determination
or udohermaphrodite : difficult to di (Y chromosome)
complete absence of fferentiate
the cervix and uterus
in a female
Absent endometrium not diagnosed by P.Ex Evaluation of endocrine

abnormalities
(estrogen & progesterone
challenge test)
Asherman syndrome not diagnosed by P.Ex HSG,
saline infusion
USG
Hysteroscopy
Treatment
 Imperforate hymen
: making a cruciate incision to open the vaginal orifice
 Transverse septum : surgical remove
 Hypoplasia or absence of the cervix in the presence of a functi

oning uterus
: surgery to repair the cervix : not successful
→ hysterctomy is required
 Vagina : absent or short

: progressive dilation is usually successful in making it
functional
Treatment
 Complete androgen insensitivity
: testes removed after pubertal development is complete to prevent
malignant degeneration
 Asherman syndrome
– removed using hysteroscopic resection with scissors or electro
cautery
– pediatric foley catheter : placed in the uterine cavity for 7~10da
ys postop
– a 2-month course of high –dose estrogen therapy with monthly
progesterone withdrawal is used to prevent reformation of adhe
sions
Amenorrhea
with Secondary Sexual Characteristics a
nd Nonanatomic Causes
Cause Cause
 Ovarian failure  Anorexia Nervosa
 Pituitary / Hypothalamic Lesions  Exercise
 Altered Hypothalamic Gonadotro  Stress-induced Disorder

pin –releasing Hormone secretion
 Obesity
 Weight Loss and Dieting
 Other Hormonal Factors
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Ovarian Failure
Causes of Ovarian failure after Development of Secondary Sexual Chracteristics

Chromosomal etiology
Iatrogenic Causes
Radiation
Chemotherapy
Surgical alteration of on blood supply
Infections
Autoimmune disorders
Galactosemia (mild form or heterozygote)
Savage syndrome
Cigarette smoking
Idiopathic
Ovarian Failure
 Normal : menopause
– Age of menopause : determined by genetic inheritance
 Premature ovarian failure

– ovarian failure <40years (1~5% of women)
– cause : decreased follicular endowment or accelerated
follicular atresia
Ovarian Failure
Cause
 Cigarette smoking
– Alters both gametogenesis and hormonogensis
– Inverse dose-response relationship with age of menopause
 Sex chromosome disorders

– Deletion of the X chromosome (Turner syndrome)
: associated with premature ovarian failure despite normal
development of the ovaries
– d/t accelerated atresia of the follicles
Ovarian Failure
Cause
 Fragile X carriers
– Cause of inherited (X-linked) mental retardation
– 4-5% of premature ovarian failure
– If premature ovarian failure is present in another family member, the chan
ce of finding a premutation increases to 15%
 Iatrogenic causes
– radiation,
sterility dose : 800cGy,
ovarian failure :150cGy in some pts. esp. >40yrs
– chemotherapy (esp. alkylating agents : cyclophosphamide)
– surgical interference with ovarian blood supply,
– infection
Ovarian Failure
Cause
 Infections
– Mumps
– Tubo-ovarian abscess
: follicular destruction and premautre ovarian failure
 Autoimmune Disorders
– Part of a polyglandular autoimmune syndrome
– Myasthenia gravis,
– Idiopathic thrombocytopenia purpura (ITP)
– Rheumatoid arthritis,
– Vitiligo,
– Autoimmune hemolytic anemia
– Diabetes mellitus
– Other autoimmune disorder
Ovarian Failure
Cause
Galactosemia
 Lack of functional galactose-1-phosphate

uridyl transferase (GALT)
 Galactose metabolites
: toxic effects on ovarian follicles causing
premature destruction
 associated cataracts, MR
Ovarian Failure
Cause
 Savage syndrome
– Gonadotropin resistance,
– Likely d/t FSH receptor dysfunction
– High level of FSH and LH levels
– Biopsy : not advised
 Autosomal gene mutations

– Associated with hearing loss in Perrault syndrome
Pituitary / Hypothalamic Lesions

Pituitary and Hypothalamic Lesions
Pituitary and Hypothalamic
Craniopharyngioma
Germinoma
Tubercular granuloma
Sarcoid granuloma
Dermoid cyst
Pituitary
Nonfunctioning adenoma
Hormone-secreting adenomas
Prolactinoma
Cushing’s desease
Acromegaly
Primary hyperthyroidism
Infarction
Lymphocytic hypophysitis
Surgical or radiologic ablations
Sheehan’s syndrome
Diabetic vasculitis
Hypothalamic Tumors
 Craniopharyngiomas (m/c),
 Germinomas,
 Tubercular or sarcoid granulomas,
 Dermoid cysts
→ prevent appropriate hormonal secretion

Pituitary Lesions
 Hypopituitarism : rare
: d/t large portion of the gland must be destroyed before decreased
hormonal secretion affects the patient clinically
– Gland destroyed by tumors (nonfunctioning or hormone secreting)
– Infarction
– infiltrating lesions such a lymphocytic hypophysitis, granulomato

us lesions, and surgical or radiologic ablations

Pituitary Lesions
 Sheehan syndrome
– Associated with postpartum necrosis of the pituitary resu

lting from a hypotensive episode
– Pituitary apoplexy : severe form
– Severe : retro-orbital headache or abnormalities in visual

fields and visual acuity
– Mild : not lactate, lose pubic and axillary hair,

not menstruate after delivery
Pituitary Lesions
 Diabetic vasculitis and sickle cell anemia
 Prolactinomas
Altered Hypothalamic Gonadotropic-releasing Hor

mone Secretion
Abnormalities Affecting Release of Gonadotropin-Releasing Hormone
Variable estrogen status Euestrogenic states
Anorexia nervosa Obesity
Exercise-induced Hyperandrogenism
Stress-induced Polycystic ovary syndrome
Pseudocyesis Cushing’s syndrome
Malnutrition Congenital adrenal hyperplasia
Chronic diseases Androgen-secreting adrenal tumors
Diabetes mellitus Androgen-secreting ovarian tumors
Renal disorders Granulosa cell tumor
Pulmonary disorders Idiopathic
Liver disease
Chronic infections
Addison’s disease
Hyperprolactinemia
Thyroid dysfunction
Altered Hypothalamic Gonadotropic-releasing Ho

rmone Secretion
GnRH : Gonadotropin releasing hormone

TRH :Thyrotropin releasing hormone
CRH:corticotrophic releasing hormone,
ACTH adrenocorticotrophic hormone,
GHRH : Growth hormone releasing hormone
Altered Hypothalamic Gonadotropic-releasing H
ormone Secretion
 Pulsatile secretion of GnRH caries in

both frequency and amplitude through
out the menstrual cycle and tightly reg
ulated
 Follicular phase
: frequency and amplitude of pulses↑
 luteal phase
: frequency ↓ and amplitude↑↑↑
– pulse frequency ↓
: LH secretion ↓& FSH ↑
– Important aspect of enhancing FS
The pulsatile secretion of GnRH in the follicular
H availability in late luteal phase
and luteal phases of the cycle
Altered Hypothalamic Gonadotropic-releasing H

ormone Secretion
 Abnormal secretion of GnRH : 1/3 of patients with amenorrhea
 Chronic disease, malnutrition, stress, psychiatric disorders, ex

ercise
: inhibit GnRH pulses → altering the menstrual cycle.
 Hyperprolactinemia, Cushing disease (excess ACTH), acromeg

aly (excess GH),
: secreted excess pituitary hormones
→ inhibit GnRH secretion
GnRH pulsatility ↓ : severe amenorrhea

Less severe alterations in GnRH pulsatility : anovulation
Slight defects in the pulsatility : luteal phase defect
Altered Hypothalamic Gonadotropic-releasing Ho

rmone Secretion
 Leptin
– hormone secreted by adipocytes that is involved in energy

hemostasis
– Receptors : in the hypothalamus and bone
– correlate with nutritional changes and body mass index
– Leptin level ↓
: associated with hypothalamic amenorrhea
Weight Loss and Dieting
Loss of 10% body mass in 1year
: associated with amenorrhea

Anorexia Nervosa
 Eating disorder : affects 5% ~ 10% of adolescent women in the US
 Criteria for diagnosis

(Diagnostic and Statistical Manual of Mental Disorders -DSM-IV-)
– Refusal to maintain body weight above 15% below normal
– An intense fear of becoming fat
– Altered perception of one’s body image
(ie. Patients see themselves as fat despite being underweight)
– Amenorrhea
Anorexia Nervosa
 Attempt to maintain their low body weight by food restriction, i

nduced vomiting, laxative abuse, and intense exercise.
 Mortality rate : 9%
 Combinations of restrictive and binge eating
 Binge eating : associated with bulimia consisting of vomiting, l

axative abuse, and diuretics to control weight.
 Signs of bulimia : tooth decay, parotid gland hypertorph (chip

munk jowls), hypokalemia, metabolic alkalosis
Exercise
 Decreased in the frequency of GnRH pulses
 Assesed by measuring a decreased frequency of LH pulse
 Hypoestrogenic state
 Runners and ballet dancers > swimmer (high risk)

(differences in body-fat content have been used to explain the different rates of
amenorrhea by sport)
– minimum of 17% of body fat is required for the initiation of menses
– 22% body fat for the maintenance of menses
 Higher-intensity training, poor nutrition, stress of competition, an

d associated eating disorders increase an athlete’ risk for menstr
ual dysfunction
– Female athlete triad

• amenorrhea,
• osteoporosis,
• eating disorder
Stress-induced Disorders
Caused by abnormalities in neuromodulation in hypothalamic

GnRH secretion
(similar to those that occur with exercise and anorexia nervosa )
Obesity
 >8.4% in women above 75% ideal body weight : menstrual disorder
 Obese women
– Excess number of fat cells in which extraglandular aromatizatio

n of androgen to estrogen occurs
– Lower circulating levels of sex hormone-binding globulin
: allows a larger proportion of free androgens to be converted to estro
ne
– Excess estrogen : risk for endometrial cancer for these women.
Other Hormonal Factors

 PCOS
– irregular bleeding rather than amenorrhea
– one of the most common causes of amenorrhea
– result of peripheral alteration in IGF-1, androgen, estrogen level
s, which leads to hypothalamic dysfunction
 Elevations in androgens (eg. Sertoli-Leydig, hilus and lipoid cell tu

mors) and estrogens (e.g. granulosa cell tumors) by ovarian tumor
s
: lead to abnormal menstrual patterns, including amenorrhea
 Excess secretion of GH, TSH, ACTH and prolactin from pituitary gla
nd
: cause abnormal feedback inhibition of GnRH secretion leading to amenorrhea
Amenorrhea
with Secondary Sexual Characteristics
and Nonanatomic Causes
Diagnosis
Treatment
Diagnosis
 Pregnancy test (urine or S-hCG)
 Pregnancy (-)
– Serum TSH
– Serum prolactin
– FSH levels
– Estrogen status
– Imaging of the pituitary and hypothalamic assessment as ne

cessary
Diagnostic work-up
Pregnancy test (-)
Progesterone challenge test
• medroxyprogesterone acetate, (MPA)
5mg or 10mg for 10dsys poCheck TSH & prola
ctin level
100~200 mg progesterone in oil IM
→ withdrawal bleeding within 2~10days
Both normal after the last dose Normal PRL Normal TSH
abnormal TSH Abnormal PRL
• Serum estradiol > 40pg/mL
Progesterone
Thyroid disease
challenge test
•2.5mg conjugated estrPRL < 100pg/mL PRL >100pg/mL
Withdrawal bleeding (+) Withdrawal bleeding(-) ogen or 2mg micronize

d estradiol, for 25days
Normogonadotropic hyp Estrogen /Progesteron c
with 5~10mg of MPA for Perform MRI to evaluate f
Consider others
ogonadism hallenge test the last 10days or prolactinoma
Withdrawal Withdrawal MRI (-)

bleeding (+) bleeding(-) Consider others
Asherman syndrome confirme

Check FSH & Outflow d by showing filling defects on
LH level obstruction
HSG or by visualizing adhesion
s with hysteroscopy
FSH>20IU/L
FSH&LH<5 IU/L
LH > 40IU/L
Hypergonadotropic hyp MRI to evaluate for

ergonadism pituitary tumor
Normal MRI
Hypogonadotropic hypo
gonadism
Diagnosis
Follicle-stimulating Hormone Levels
 S-FSH > 25~40mIU/mL (on at least two blood samples)

: hypergonadotropic amenorrhea
 Dx for cause of ovarian failure

– History : chemotherapy, radiation therapy
– Galactose 1 phosphate uridyl transferase (GALT) level
– Fragile X carrier status
– Karyotype (<30years of ages) : presence of a Y cell line
– autoimmune disorder
– Ovarian biopsy : not advised
Diagnosis
Follicle-stimulating Hormone Levels
 Extent of an autoimmune workup required for a patient with ovari
an failure
– Screening with nonspecific test (ANA, RA, ESR)
– Normal PTT : exclude lupus anticoagulant
– Serum electrolytes, calcium, phosphorus concentrations
: evaluate possibility that parathyroid autoantibodies are active
– TSH, antithyroglobulin antibodies, antimicrosomal antibodies
– 24hr urinary free cortisol
: detect the presence of antiadrenal antibodies
– Parietal cell antibodies, islets of Langerhans antibodies and antiad
renal antibodies : unclear
→ repeated yearly d/t transient nature of autoimmune disorders
Diagnosis
Assessment of the Pituitary and Hypothalamus
 Hypoestrogenic & FSH level : not high

→ pituitary and hypothalamic lesions should be excluded
– A complete neurologic examination
– CT or MRI
– After anatomic lesions have been excluded, the patient’s history

of weight changes, exercise, eating habits, body image, and career o
r school achievements are important factors in differentiating anorexi
a nervosa, malnutirition, obesity or exercise-induced or stress-induce
d menstrual disorders.
Diagnosis
 Hypothalamic dysfunction caused by chronic disease, anorexia n

ervosa, stress, and malnutrition
– may be more severe or
– may exist for a more prolonged time in hypoestrogenic
patients than in euestrogenic patients.
 Appropriate clinical findings

– Androgen levels (hirsutism…)
– IGF-1 levels : Acromegaly
– 24hr urinary cortisol
: Cushing syndrome ( truncal obesity, hypertension, erythm
atous striae)
Treatment
 Thyroid abnormalities
: thyroid hormone, radioactive iodine, antithyroid drugs
 Hyperprolactinemia
: dopamine agonists (bromocriptine or cabergoline)
 Surgery for particularly large pituitary tumors
 Ovarian failure : hormone replacement
 Y cell line(+) : Gonadectomy
 Surgical removal, radiation therapy, or a combination of both is

generally advocated for treatment of central nervous tumors oth
er than prolactinoma
Treatment
Treatment of amenorrhea associated with hypothalamic dysfunction
 Hormonally active ovarian tumors : surgical removed
 Obesity, malnutrition or chronic disease, Cushing syndrome and

acromegaly : specially treat
 Pseudocyesis and stress-induced amenorrhea

: respond to psychotherapy
 Exercise–induced amenorrhea
: improve with moderation of activity and weight gain, when appro
priate
 Anorexia nervosa : demands a multidisciplinary approach

Treatment
Treatment of amenorrhea associated with hypothalamic dysfunction
 Chronic anovulation or PCOS : treated after identifying the desire

s of the patient (menstruation, hirsutism or infertility)
– endometrium should be protected from the environment of un

opposed estrogen
– oral contraceptives or progestin
– Estrogen +progestin replacement for successful menstrual re

gulation and prevention of osteoporosis
Medroxyprogessterone acetate (10mg for 10days/month)
 Congenital adrenal hyperplasia

: glucocorticoid administration (ie. Dexamethasone 0.5mg at bedtime)
Treatment
Hirsutism
 R/O androgen-secreting tumors, congenital adrenal hyperplasia
 Aim of treatment : decreasing coarse hair growth
– Oral contraceptives
– Antiandrognes
• Spironolactone Flutamide
• Cyproterone acetate (strong progestin)
– GnRH Agonist
• Add-back therapy
– 5α- reductase inhibitors
– Eflornithine hydrochloride (topical cream)

Treatment
Ovulation Induction
Clomiphene citrate : 1st choice for ovulation induction

 Relative safety, efficacy, route of administration (oral), relatively
low cost
 Indication
– adequate levels of estrogen and normal FSH and prolactin,
– inappropriate gonadotropin release
(an increased LH-to-FSH ratio ie. PCOS)
 Pregnancy rate : 40%
 Rate of expected ovulation : 80%

Treatment
Ovulation Induction
Clomiphene citrate : 1st choice for ovulation induction

 Contraindication
: pregnancy, liver disease, pre-existing ovarian cysts
 Side effects
: hot flashes(>11% of pts), poorly understood visual symptoms
 Incidence of multiple gestation : 6.25~12.3%
 Regimen
– 50mg daily for 5days
– beginning on the 3rd~5th day of menstrual or withdrawal blee
ding
Treatment
Ovulation Induction
 Longer courses of clomiphene citrate

: adjunctive therapy with glucocorticoids and hCG
 PCOS : insulin resistance – insulin sensitizing agents

(biguanide metformin and thiazolidinediones)
 Injectable gonadotropins
– FSH
– Complication : multiple pregnancy (10~30%)
 GnRH
: chronic anovulation associated with low levels of estrogen and
gonadotropins
 Ovarian failure and desire pregnancy ; oocyte donation

 Continual pulsatile secretion of GnRH is necessary
 d/t extremely short half life (only 2~4 minutes) – rapid proteolyti
c cleavage
 Continual infusion : gonadotropin secretion (-) downregulation
 - the number of gonadotroph cell surface GnRH receptor ↓
 Palsatile pattern : led to physiologic secretion patterns and folli
cular growth, upregulate or autoprime
 - The gonadotroph to increase its number of GnRH receptors
 Pulsatile secretion of GnRH caries in both frequency and amplit
ued throughout the menstrual cycle and tightly regulated
 Follicular phase : increase in both frequency and amplitude of
pulses
 During luteal phase : progressive lengthening of the interval be
tween pulses and amplitude higher

Chapter 27. Amenorrhea: Berek & Novak's Gynecology 14 Edition (P 1035 1068) R3 Jung Mi Byun

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Chapter 27. Amenorrhea: Berek & Novak's Gynecology 14 Edition (P 1035 1068) R3 Jung Mi Byun

Cargado por

Copyright:

Formatos disponibles

Chapter 27.

Berek & Novak’s Gynecology

– at age 13years when there is no visible secondary sexual

– at age 15years in the presence of normal secondary sexual

Normal menstrual cycle

hypothalamus, pituitary, ovary, outflow tract, feedback mechanism

→ bleeding cannot occur. (Amenorrhea)

 Amenorrhea : 3~4% of reproductive age women, not pregnant.

Physical exam HCG - HCG +

Normal Absent uterus Pregnancy

Karyotype Karllman’s syndrome

Secondary if risk of Physical exam

TSH, PRL, FSH, Mullerian anomaly

Normal TSH Abnormal TSH

High PRL Hyperthyroidism

Normal PRL Hyperprolactinemia

Normal FSH High FSH

Normal estrogen Low estrogen Ovarian failure-

Chronic disease Hypothalamic Pituitary-hypothalamic

 Absence of secondary sexual characteristics

 Absence of a uterus suggests certain enzyme deficiencies and i

 Other causes of Primary Ovarian Failure

 Other Hypothalamic / Pituitary Dysfunctions

Abnormal physical examination

 Associated with genetic abnormalities

 Syndrome of gonadal dysgenesis or Turner syndrome

– Deletion of the long arm of the X chromosome(Xq-) Xq13~Xq26

– Deletion of the short arm of the X chromosome (Xp)

< Swyer syndrome >

 Mixed gonadal dysgenesis

– Ambiguous genitalia with a streak gonad on one side and a

– SRY gene mutation (small proportion )

 Follicle-stimulating Hormone receptor Mutation

Other Causes of Primary Ovarian Failure

 Combination of radiation and other chemothrapeutic agents

 Pituitary disorder associated with inadequate production or rel

 Central Nervous System Tumors

 most common manifestation of hypogonadotropic hypogonadis

 physiologic delay of puberty are usually short for their chronolo

 normal for their bone age

 2nd most common hypogonadotropic hypogonadism

 insufficient pulsatile secretion of GnRH (Kallmann syndrome), whi

 caused by developmental or genetic defects, inflammatory proces

 normal height for their age,

 Gnoadotropin-releasing Hormone Receptor Mutations

 Follicle-stimulating Hormone Deficiency

 male differentiation of the urogenital sinus a

 GnRH receptor : G-protein-coupled receptor

 Abnormal GnRH function

 17% of sporadic cases of idiopathic hypogonadotropic

 FSH↓ LH ↑ : distinguished from other hypoestrogenism

 Low serum androgen levels

Other Hypothalamic / Pituitary Dysfunctions

 Weight loss  Polycystic ovarian syndrome (PCOS)

 Anorexia nervosa  Cushing syndrome

 Excess ecercise  Hyperprolactinemia

 Chronic disease  infiltrative disorders of the central ner

Coarctation of the aorta (30%)

All forms of gonadal failure

→ cyclic estrogen and progestin therapy

: to initiate, mature, and maintain 2nd sexual characteristics

 estrogen +progestin (medroxyprogeste Medrosyprogesterone acetate